Pharmacologic management of neuropathic pain

Pharmacologic Management of Neuropathic Pain yyy Debra B. Gordon, RN, MS* and Georgette Love, MSN, APRN†

y

ABSTRACT:

The mechanisms underlying the pathogenesis of neuropathic pain are complex but are gradually coming to light. Agents that have been found effective in a variety of neuropathic pain conditions include drugs that act to modulate (a) sodium or calcium channels, (b) N-methyl-D-aspartate receptors, (c) norepinephrine or serotonin reuptake, (d) opioid receptors, and (e) other cellular processes. Clinical trials have primarily evaluated these treatments for postherpetic neuralgia and painful diabetic neuropathy, the two most common types of neuropathic pain. Nonetheless, the identification of effective treatment regimens remains challenging, often because multiple mechanisms may be operating in a given patient giving rise to the same symptom. Alternatively, a single mechanism may be responsible for multiple symptoms. Currently available diagnostic tools are inadequate to determine the best treatment using a mechanism-based model. Clinically, drug treatment of neuropathic pain is often a matter of treatment trials. This article presents a summary of available clinical information on first-line and lesser-known treatments for neuropathic pain. © 2004 by the American Society for Pain Management Nursing

From *University of Wisconsin Hospital and Clinics, Madison, WI, and †University of Utah Health Sciences Center, Salt Lake City, UT. Address correspondence and reprint requests to Debra B. Gordon, RN, MS, Senior Clinical Nurse Specialist, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, F6/ 121-1535, Madison, WI 53792. E-mail: [email protected] 1524-9042/$30.00 © 2004 by the American Society for Pain Management Nursing doi:10.1016/j.pmn.2004.10.005

Neuropathic pain is a complex phenomenon that may involve several independent pathophysiologic mechanisms in both the peripheral and central nervous systems (Table 1). The precise mechanisms of neuropathic pain and the relationships between these mechanisms and the signs and symptoms exhibited in patients are not fully understood. It may be that one mechanism produces several symptoms or that one symptom may be due to several mechanisms (Harden & Cohen, 2003). There are no diagnostic tools to identify mechanisms, so patients are generally grouped and treated based on signs and symptoms clusters or disease states. Because of these complexities, neuropathic pain is universally recognized as one of the most difficult pain conditions to treat. Attempts are being made to sort out the response to various analgesics based on symptoms, drug challenges, diseases, and tissues to make treatment more selective and effective. However, in many patients, multiple and overlapping mechanisms likely exist, and the choice of pharmacologic treatment is most often determined through a series of empiric trials in each individual. Pain Management Nursing, Vol 5, No 4, suppl 1 (December), 2004: pp 19-33

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TABLE 1. Mechanisms of Neuropathic Pain Peripheral nervous system ● Sensitization of peripheral neurons ● Unmasking of silent nociceptors ● Collateral sprouting ● Increased activity of damaged axons and their sprouts ● Invasion of dorsal root ganglia by sympathetic postganglionic fibers Central nervous system ● Hyperexcitability of central neurons (central sensitization) ● Reorganization of synaptic connectivity in spinal cord and elsewhere within the central nervous system ● Disinhibition-removal of tonic descending inhibitory activity and other mechanisms Note: Reproduced from Ashburn, M.A., & Staats, P.S. Management of chronic pain. The Lancet, 353, 1865–1869 (used with permission).

Medications used to treat neuropathic pain have traditionally been categorized by their drug class (antidepressant, anticonvulsant, anti-arrhythmic, analgesic [opioid or nonsteroidal anti-inflammatory], topicals). Thus far, medication trials have not been able to find different responses of symptoms to different drugs, except in postherpetic neuralgia (PHN) where patients with allodynia and no sensory loss responded to topical anesthetics, whereas patients with major sensory loss did not (Fields, Rowbotham, & Baron, 1998). A recent pilot study of a topical anesthetic in painful diabetic neuropathy (PDN), however, found comparable improvement

with and without allodynia, so the literature is clearly still evolving (Barbano, et al., 2004). Results from clinical trials of individual agents within a drug class are often generalized in clinical practice when selecting a medication to treat neuropathic pain. For example, a clinician might use amitriptyline to treat all forms of neuropathic pain because of a number of positive clinical trials of amitriptyline in PHN. Alternatively, a clinician may choose to treat a particular pain syndrome only with drugs that have been examined in a particular population (e.g., carbamazepine in patients with trigeminal neuralgia). However, both of these approaches are inadequate because they imply that all drugs in a particular class exert their effects through similar mechanisms or that similar mechanisms exist in all individuals with a particular pain syndrome. Work is ongoing to more clearly stratify medications used in the treatment of neuropathic pain by their precise mechanism of action (Beydoun & Backonja, 2003) and to determine if a particular symptom can be modulated by a drug with a specific action (Jensen, Gottrup, Sindrup, & Bach, 2001). Although mechanistic stratification of neuromodulator medications is in its infancy, four categories have been suggested (Table 2), including sodium channel modulators thought to be involved in peripheral sensitization, calcium flux modulators that operate at the level of the dorsal horn, drugs that enhance descending inhibition through actions on serotonin, norepinephrine, and opioid transmission (Beydoun & Backonja, 2003), and drugs that modulate central sensitization by their effects on NMDA receptors.

TABLE 2. Mechanistic Stratification of Drugs Used to Treat Neuropathic Pain Drugs That Modulate Peripheral Sensitization by Inactivation of Voltage-Dependent Sodium Channels

Drugs That Modulate Central Sensitization by Interacting with High-Threshold NType Calcium Channels

Carbamazepine Lamotrigine Lidocaine Mexiletine Phenytoin Tricyclic antidepressants

Gabapentin Lamotrigine Carbamazepine

Drugs That Enhance the Descending Inhibitory Pathways Opioids Selective norepinephrine reuptake inhibitors (SNRIs) Selective serotonin reuptake inhibitors (SSRIs) Tramadol Tricyclic antidepressants

Drugs That Modulate Central Sensitization by Their Effects on the NMDA Receptors Dextromethorphan Ketamine Methadone

Pharmacologic Management of Neuropathic Pain

FIRST-LINE TREATMENT OPTIONS Although many medications are useful in the treatment of neuropathic pain, there is no generally accepted consensus on the most appropriate treatment choice for any given patient. Although the existing literature shows that no one drug appears to be more effective than another (Sindrup & Jensen, 1999), even this conclusion is tenuous because of the limited number of comparative studies. In an effort to consider clinical efficacy, adverse effects, influences on quality of life, and cost, recommendations for first-line medications to treat neuropathic pain were developed by a committee of the Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain (Dworkin, Backonja, et al., 2003). Systematic reviews of available evidence, published clinical guidelines, and the investigators’ clinical experience were used to gain consensus. The consensus recommendations identify the following agents (listed in alphabetical order) as first-line treatment options in neuropathic pain: gabapentin, the 5% lidocaine patch, opioid analgesics, tramadol hydrochloride, and tricyclic antidepressants. Shortcomings of the recommendations were acknowledged and include a lack of accepted diagnostic criteria for neuropathic mechanisms, incomplete understanding of the precise actions of many of the medications, a limited number of randomized controlled trials, and methodologic shortcomings of some of the available trials. The number of head-to-head comparative studies is limited, making it impossible to position individual medications by rank. First-line medications (Table 3) are not listed or recommended in any order of priority. As such, the choice of agent must be based on comprehensive patient assessment with consideration of multiple factors, including individual risk factors for adverse events, comorbidities, cost, patient response, and an acceptance that combinations of medications may be necessary. A review of the evidence that supports the first-line medications as well as a synopsis follows. Gabapentin Gabapentin (Neurontin; Pfizer Inc, New York, NY), originally developed as an antiepilepsy drug, is also effective for neuropathic pain. A recent systematic review identified eight published, double-blind, randomized, placebo-controlled clinical trials of gabapentin for neuropathic pain (Dworkin, Backonja, et al., 2003). Patients enrolled in these studies had PHN, PDN, mixed neuropathic pain syndromes, phantom limb pain, Guillain-Barré syndrome, and acute and chronic pain from spinal cord injury. Compared with

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other systemic drugs for neuropathic pain, gabapentin has an excellent tolerability and safety profile. Side effects include somnolence, dizziness, gastrointestinal symptoms, mild peripheral edema, ataxia, and fatigue (Rowbotham, Harden, Stacey, Bernstein, & MagnusMiller, 1998; Backonja et al., 1998). Cognitive impairment and problems with gait or balance may be observed, and this is a particular concern in elderly patients (Dworkin, Backonja, et al., 2003). Side effects typically subside within 2 weeks. Unlike many other drugs, gabapentin is not metabolized in most people and is excreted unchanged in the urine. It does not bind to plasma proteins, induce hepatic enzymes, show drug-drug interactions, or produce any known end-organ cellular toxicity (Backonja & Glanzman, 2003). Because of its renal excretion in patients with renal insufficiency, the dosage should be adjusted. To minimize adverse effects and maximize patient adherence, gabapentin is usually administered initially at low dosages, (e.g., 100 mg to 300 mg in a single dose at bedtime, or 100 mg to 300 mg three times daily) followed by titration every 1 to 7 days in 100 mg to 300 mg increments, as tolerated. The target therapeutic dose for analgesia appears to range between 1,800 and 3,600 mg/day administered in divided doses (e.g., 600 to 1,200 mg three times daily (Dworkin, Backonja, et al., 2003; American Pain Society, 2004). Topical 5% Lidocaine Patch The 5% lidocaine patch (Lidoderm; Endo Pharmaceuticals, Chadds Ford, PA) is a peripherally acting topical analgesic. Its mechanism of action is incompletely understood, but it is believed to exert its effect by delivering amounts of lidocaine sufficient to block sodium channels on small damaged pain fibers but insufficient to interfere with normal conduction of impulses in large sensory fibers. When applied to a painful area, it produces local analgesia, with a minimum risk of systemic side effects and drug interactions (Gammaitoni, Alvarez, & Galer, 2002). Two published, double-blind, randomized, vehicle-controlled trials have evaluated the 5% lidocaine patch in patients with PHN (Rowbotham, Davies, Verkempinck, & Galer, 1996; Galer, Rowbotham, Perander, & Friedman, 1999). In another double-blind, randomized, vehiclecontrolled trial, the patch was evaluated as add-on therapy for the treatment of chronic painful peripheral neuropathic pain syndromes from various causes and was found to be effective in reducing both ongoing pain and allodynia (Meier et al., 2003). Like gabapentin, the 5% lidocaine patch has an excellent tolerability and safety profile. The skin under the patch maintains normal sensation with no numbness, unlike the effect experienced when a local anesthetic is infiltrated sub-

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TABLE 3. First-Line Medications for Neuropathic Pain Medication (Brand Name)

Primary Site/Mechanism of Action

Gabapentin (Neurontin; Pfizer)

Unknown, believed to be sodium channel blockade At least partially central Ca⫹⫹ channel Unknown, believed to be sodium channel blockade Central modulatory

5% lidocaine patch (Lidoderm; Endo Pharmaceuticals) Opioids: morphine, oxycodone, methadone*, others

Tramadol hydrochloride† (Ultram [Ortho McNeil], others)

Central modulatory norepinephrine and serotonin reuptake inhibitor with metabolite that is ␮ opioid agonist

Tricyclic antidepressants: amitriptyline (Elavil; Astra Zeneca) nortriptyline (Pamelor; Mallinckrodt) desipramine (Norpramin; Aventis) doxepin (Adapin [Fisons], Sinequan [Pfizer]) imipramine (Tofranil; Mallinckrodt)

Na⫹ channel Central modulatory Inhibits norepinephrine and serotonic reuptake

Dosing/Titration

Side Effects

1800–3600 mg per 24 hours in divided dose 3⫻; daily

Somnolence Dizziness Gastrointestinal symptoms Mild peripheral edema Ataxia Mild skin reactions (e.g., erythema or rash)

Maximum of 4 patches used simultaneously for a maximum of 18 hours No maximum with careful titration; consider evaluation by pain specialist at doses ⬎20– 180 mg/d by mouth morphine equivalents 50–100 mg 2–3⫻ daily, maximum of 400 mg/d

10–25 mg in single dose at bedtime and then titrated every 3 to 7 days by 10, to 25 mg/d, to doses of 75 to 150 mg/d as tolerated

Constipation Sedation Nausea Pruritus Respiratory depression Fewer opioid side effects such as constipation and respiration depression. Psychiatric reactions, ataxia, numbness in limbs, dysphoria, tremulousness, confusion, hallucinations, seizures Sedation Anticholinergic effects (e.g., drug mouth, constipation, other) Balance problems Cognitive impairment Postural hypotension Weight gain Cardiac events (arrhythmia, tachycardia, stroke, acute myocardial infarction) Inhibition of certain antihypertensive drugs

*Methadone also produces N-methyl-D-aspartate receptor antagonism. †Tramadol not considered first line in more recent drug trial reviews because of numbers needed to treat to achieve ⬎50% pain relief for tramadol is 4.3 compared with 2.7 for anticonvulsants and 3.4 for antidepressants in review of clinical studies by Backonja M. M., Serra J. (2004). Pharmacologic management part 1: better-studies neuropathic pain diseases. Pain Medicine, 5, S28 –S47. Adapted from Dworkin, et al. (2003). Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Archives of Neurology, 60, 1524 –1534.

cutaneously. Another clinical benefit is that the patch acts as a protective barrier for hypersensitive skin (Bajwa & Ho, 2001). Side effects include mild skin reactions (e.g., erythema, rash). There is minimal systemic absorption (3% ⫾ 2%; Lidoderm prescribing information), and accumulation of lidocaine does not occur with a dosage schedule of up to four patches for up to 18 hours per day (Barbano, et al., 2004). Nonetheless, systemic absorption must be considered in patients taking oral class I antiarrhythmic drugs, such as mexiletine hydrochloride (Dworkin, Backonja, et al., 2003). Patches should only be applied to intact

skin but may be cut to fit the painful area without worry of systemic absorption (Gordon, 2003). Opioids Opioids have been used since ancient times for the treatment of pain. Results of clinical trials for neuropathic pain are mixed (Dellemijn, 1999; Gimbel, Richards, & Portenoy, 2003; Rowbotham, Twilling, Davies, Reisner, Taylor, & Mohr, 2003). It has been noted that numerous factors can influence the efficacy of opioids. Particular opioids may be more effective for particular types of pain, particular patients, or

Pharmacologic Management of Neuropathic Pain

when used in particular drug regimens (Christo, 2003). In clinical practice, barriers to opioid use include fear of addiction (on the part of both patients and clinicians), fear of side effects (by patients and clinicians), and regulatory and/or prescribing issues (for clinicians; Gilron & Bailey, 2003). However, clinicians have observed that some patients with neuropathic pain do respond to opioids. In light of several recent, well-controlled trials, the consensus of clinical opinion is evolving, and a more balanced view of the use of opioids in neuropathic pain is emerging. Three well-designed studies have evaluated the use of controlled-release oxycodone (OxyContin; Purdue Frederick, Norwalk, CT) in PHN (Watson & Babul, 1998) and PDN (Gimbel, Richards, & Portenoy, 2003; Watson, Moulin, Watt-Watson, Gordon, & Eisenhoffer, 2003), with favorable results. Controlled-release morphine (e.g., MS-Contin [Purdue Frederick], Oramorph-SR, Kadian [Faulding-Purepac, Elizabeth, NJ], Avinza [Elan Pharma, Cambridge, MA]) has shown analgesic efficacy for phantom limb pain (Huse Larbig, Flor, & Birbaumer, 2001) and for PHN (Raja et al., 2002). In addition, levorphanol (e.g., Levo-Dromoran; ICN Pharmaceuticals, Costa Mesa, CA) was recently found to be effective for patients with a variety of peripheral and central neuropathic pain syndromes (Rowbotham, Twilling, Davies, Reisner, Taylor, & Mohr, 2003). When prescribing opioid analgesics, clinicians must understand the differences between addiction, physical dependence, and tolerance (Table 4). Initial evaluation and ongoing assessment of patients on opioid therapy should include documentation of the treatment plan and outcomes, discussion of the risk of side effects and misuse or abuse, and clearly established expectations for patient adherence to the treatment regimen. The most common side effects of opioid analgesia are constipation, sedation, and nausea. In elderly patients, cognitive impairment and problems with mobility can occur, which may contribute to an increased risk of falls. Most patients become tolerant to these side effects, although constipation often persists. Regular laxative therapy can help alleviate this, as can the use of transdermal fentanyl citrate (Duragesic; Janssen Pharmaceuticals, Titusville, NJ). Transdermal fentanyl administered by a nonenteral route is less constipating because it avoids the direct effect of an opioid drug on opioid receptors in the intestinal mucosa (Staats, Markowitz, & Schein, 2004). In patients with diabetes who have concurrent cardiac and renal disease, opioids may be safer than other first-line agents (Zochodne & Max, 2003). Opioid analgesics should be used cautiously in patients with a history of substance abuse or attempted suicide. Due to the development

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TABLE 4. Definitions Related to the Use of Opioids for the Treatment of Pain Addiction Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Pseudoaddiction Pseudoaddiction is characterized by behaviors that occur when pain is undertreated, and can be distinguished from true addiction in that the behaviors resolve when pain is effectively treated. Physical Dependence Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Tolerance Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Note: Adapted from Definitions Related to the Use of Opioids for the Treatment of Pain (a consensus document from the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine; 2001).

of physical dependence and expected physiologic adaptation, discontinuation of opioids should be gradual to avoid precipitation of a withdrawal syndrome (Dworkin, Backonja, et al., 2003). Interestingly, it has been reported in surveys of physician and patient attitudes on opioid use that physicians value functional improvement more than pain relief (Turk, Brody, & Okifuji, 1994), whereas patients place a greater emphasis on pain relief (Jamison, Anderson, Peeters-Asdourian, & Ferrante, 1994). This discrepancy underscores the role of nurses in patient education and advocacy. Tramadol Tramadol (Ultram; Ortho McNeil, Raritan, NJ) has multiple analgesic actions. It is an inhibitor of norepinephrine and serotonin reuptake, and its major metabolite binds weakly to opioid receptors (Pasero & McCaffery, 2003). Positive results have been reported for tramadol in neuropathic pain, both in patients with PDN and in patients with painful conditions of polyneuropathy, including PDN (Harati et al., 1998; Sindrup, Andersen, Madsen, Smith, Brosen, & Jensen, 1999). Adverse effects include dizziness, nausea, constipa-

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tion, somnolence, headache, and orthostatic hypotension (Ahmad & Goucke, 2002). There is an increased risk of seizures in patients who have a history of seizures or who are concomitantly receiving other drugs that reduce seizure threshold (e.g., antidepressants, opioids, neuroleptics). Serotonin syndrome (tremors, restlessness, confusion, hallucinations, lifethreatening hyperthermia) may occur if tramadol is used concurrently with selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (Bailey, 2004; Mahlberg Kunz, Sasse, & Kircheiner, 2004). Respiratory depression may be seen in patients who take tramadol together with alcohol, hypnotics, psychotropic drugs, or centrally acting analgesics (Pasero & McCaffery, 2003). In addition, the dosage should be adjusted downward in patients with hepatic or renal impairment. Cognitive impairment may occur in elderly patients (Dworkin, Backonja, et al., 2003), although tramadol is usually well tolerated (Ahmad & Goucke, 2002). To minimize the likelihood of adverse effects and increase patient tolerance, it is recommended to initiate titration at a low dose, increasing the dose every 3 to 7 days, as tolerated (Dworkin, Backonja, et al., 2003). The recommended oral dosage is 50 mg to 100 mg every 4 to 6 hours with a maximum of 400 mg/day, limiting its usefulness to mild-to-moderate pain (Lewis & Han, 1997). The American Geriatrics Society recommends the maximum dosage of tramadol be kept to 300 mg per 24 hours in elderly patients. Tricyclic Antidepressants Tricyclic antidepressants (TCAs; e.g., imipramine [Tofranil; Mallinckrodt, Hazelwood, MO], amitriptyline [Elavil; Astra Zeneca, Wilmington, DE], nortriptyline [Pamelor; Mallinckrodt], desipramine [Norpramin; Aventis Pharmaceuticals, Kansas City, MO], and doxepin [Adapin; Fisons, Rochester, NY, Sinequan; Pfizer]) have an analgesic effect that is demonstrated to be independent of their antidepressant effect (Dworkin, Backonja, et al., 2003). Their analgesic effect is thought to occur primarily through inhibition of reuptake of norepinephrine (rather than serotonin) at spinal dorsal horn synapses, with secondary activity at the sodium channels (Sawynok, Esser, & Reid, 2001; Sawynok, 2003). Several well-designed trials support the use of TCAs in the treatment of pain, including neuropathic pain (PHN and PDN; Max, 1995). In clinical practice, the use of TCAs is often limited, however, by their associated side effects. The most serious side effects occur in the cardiovascular system and include postural hypotension, heart block, sinus tachycardia, arrhythmias, and slowed heart conduction (Glassman & Roose, 1994; Roose et al., 1998).

In addition, anticholinergic side effects are bothersome to many patients (e.g., dry mouth, constipation, daytime drowsiness, and urinary retention). TCAs may also cause balance problems and cognitive impairment (Dworkin, Backonja, et al., 2003), and their use has been associated with a greater incidence of hip fractures (Liu, Anderson, Mittmann, To, Axcell, & Shear, 1998). Many of these side effects are a special concern in elderly patients. Drug-drug interactions are also common. TCAs may block the effects of antihypertensive drugs (e.g., clonidine, guanethidine), and they interact with drugs metabolized by cytochrome P4502D6 (e.g., cimetidine, phenothiazines, and class IC antiarrhythmics) or that inhibit cytochrome P4502D6 (e.g., SSRIs). An increase in plasma TCA levels may result, reaching toxic levels. In addition, TCAs must be used with caution if there is a risk of suicide or accidental death from overdose (Dworkin, Backonja, et al., 2003). As with other drugs for neuropathic pain, to minimize side effects, it is recommended to initiate treatment at a low dosage, titrating to the effective range. Amitriptyline is least well tolerated and is dosed at bedtime, whereas desipramine and nortriptyline can produce insomnia and should be taken during the day (Gordon, 2003).

SECOND-LINE AND ADDITIONAL TREATMENT OPTIONS In addition to the data available for drugs considered first-line treatment, limited data are available for a number of other therapies, including some newer anticonvulsant and antidepressant drugs, corticosteroids, and topical analgesics. These options are discussed below and summarized in Table 5. Anticonvulsants Lamotrigine (Lamictal; GlaxoSmithKline, Research Triangle Park, NC), a sodium and calcium channel blocker, is a newer anticonvulsant. It has demonstrated efficacy for the treatment of neuropathic pain in multiple, randomized, controlled trials (Simpson et al., 2000; Simpson et al., 2003; Eisenberg, Luria, Braker, Daoud, & Ishay, 2001; Vestergaard, Andersen, Gottrup, Kristensen, & Jensen, 2001). A slow and careful titration is required, and there is a risk of severe rash, as well as Stevens-Johnson syndrome, a potentially fatal epidermal necrosis. More common side effects include dizziness, unsteadiness, and drowsiness (Ahmad & Goucke, 2002). Carbamazepine (Tegretol [Novartis, East Hanover, NJ]; Carbatrol) is a sodium channel blocker that is approved by the US Food and Drug Administration

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Pharmacologic Management of Neuropathic Pain

TABLE 5. Drugs Used to Treat Neuropathic Pain Not Listed in First-Line Medication Table Generic

® Brand Name

Anticonvulsants: Carbamazepine Tegretol Carbatrol

Lamotrigine

Lamictal

Oxycarbazepine Trileptal

Possible Mechanism Na⫹ channel

Na⫹ channel N-type calcium

N-type Ca⫹⫹ channel GABA ligand Unknown

Dose Range

400-800 mg/d divided 2–4⫻ Nausea is most common; drowsiness, dizziness daily, maximum 1,600 mg/d therapeutic serum level 4– Rare but serious blood dyscrasias (aplastic anemia, 12 ␮g/mL Start low (100 mg twice daily), agranulocytosis) go slow 25-500 mg/d (in 2 divided Dizziness, ataxia, somnolence doses) and headache, rash, Stevens Start low (25 mg twice daily), Johnson (life-threatening go very slow epidermal necrosis), irritability, insomnia, rare anemia 900-2, 100 mg/day (in 2 Drowsiness, dizziness, divided doses) headache, nausea, diarrhea 150-300 mg twice daily Dizziness, somnolence, peripheral edemas and dry mouth Somnolence, anorexia, dizziness, 200-600 mg/day Start low (50 mg twice daily), headache, nausea, and go very slow agitation/irritability, nephrolithiasis, weight loss, nausea, skin eruptions including Stevens-Johnson syndrome

Pregabalin

Not yet available

Zonisamide

Zonegran

Mixed Na⫹ and Ca⫹⫹

Paxil

SSRI-inhibits presynaptic reuptake of serotonin but not noradrenaline

Citalopram

Celexa

SSRI

Venlafaxine

Effexor

Bupropion

Wellbutrin

SNRI-inhibits norepinephrine, serotonin, and dopamine reuptake Unknown, inhibits 100-150 mg 2–3⫻ daily neuronal uptake of norepinephrine, serotonin, and dopamine

Duloxetine

Cymbalta

Antidepressants: Paroxetine

SSRI and SNRI

Local anesthetics/antiarrhythmics: Lidocaine Generic Na⫹ channel

Side Effects

20-50 mg by mouth once daily increase by 10 mg/d every week

Nausea, somnolence, withdrawal syndrome, serotonin syndrome, mania, hyponatremia, sexual dysfunction, extrapyramidal symptoms, worsening depression 20-40 mg orally daily Dry mouth, nausea, somnolence, insomnia, headache, tremor, increased sweating, sexual dysfunction 37.5-75 mg by mouth 2–3⫻ Hypertension, dizziness, daily, increase dose every 4 somnolence, headache, days, maximum 375 mg/d seizure, suicidality, worsening depression

20-60 mg daily

1-5 mg/kg IV single injection or continuous infusion

Agitation, anxiety, insomnia often occur initially. Fever, dry mouth, headache, dizziness; urinary frequency, nausea, constipation, tremor, sweating, Stevens-Johnson syndrome and erythema multiforme, Seizures with overdose Nausea, somnolence, dizziness, constipation, dry mouth, hyperhydrosis, decreased appetite, and asthenia Lightheadedness, nausea, vomiting, paresthesia, cardiovascular toxicity with high serum levels, cardiac conduction block

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TABLE 5. Drugs Used to Treat Neuropathic Pain Not Listed in First-Line Medication Table (Continued) Generic Mexiletine Other Clonidine*

® Brand Name

Possible Mechanism

Dose Range

Side Effects

Mexitil

Na⫹ channel

200-450 mg twice daily

Dyspepsia, diarrhea, dizziness, tremor, coordination problems, insomnia, palpitations

Centrally acting ␣- 0.1-0.3 mg patch every 3 Dry mouth, drowsiness, adrenergic agonist days increase every 12 days dizziness, hypotension, severe rebound hypertension Drowsiness, dizziness, Baclofen* Baclofen ␥-Aminobutyric acid 5 mg 3⫻ daily for 3 days, paresthesia, headache, tablets (GABA-B) receptor increase to 10 mg 3⫻ daily hypotonia, CNS depression, for 3 days, then in similar agonist, interferes respiratory failure, seizures, with the release of increments and intervals physical dependence until either a dose of 20 mg excitatory 3⫻ daily is reached or until neurotransmitters the desired therapeutic and inhibits monosynaptic and effect is obtained. polysynaptic transmission at the spinal cord level. It may also act at supraspinal sites producing CNS depression Burning, stinging, erythema, Capsaicin Zostrix Depletes substance Topical cream, apply 2–4⫻ daily thermal hyperalgesia erythema, P from sensory thermal hyperalgesia nerves, also partial or complete degeneration of axon terminals or neuron over time (calcium–dependent desensitization) Doses of botulinum toxins A Edema, erythema, and pain at Botulinum toxin Myobloc, Neuromuscular injection site and B are expressed in NeuroBloc blockade by terms of units, which have inhibiting the not been standardized calcium-ion between preparations mediated release Doses are therefore specific of acetylcholine at to each individual the motor nerve terminals, resulting preparation in a diminished endplate potential and subsequent flaccid paralysis for 2–4 months Catapres

Note: GABA ⫽ ␥-Aminobutyric acid; CNS ⫽ central nervous system; IV ⫽ intravenous; SNRI ⫽ Selective norepinephrine reuptake inhibitor; SSRI ⫽ Selective serotonin reuptake inhibitor. *Clonidine and baclofen are also administered by the epidural and intrathecal route.

(FDA) for the treatment of trigeminal neuralgia. It has long been used for the treatment of epilepsy and has also been studied for the treatment of PDN, and, in anecdotal reports, for PHN (Ahmad & Goucke, 2002). Common side effects include nausea, drowsiness, and dizziness.

Pregabalin, a ␥-aminobutyric acid (GABA) analog, has been found effective in relieving pain and improving sleep in patients with PHN (Dworkin, Corbin et al., 2003). This study was a double-blind, randomized clinical trial in 173 patients with PHN who had a rash that persisted for at least 3 months. Patients were treated

Pharmacologic Management of Neuropathic Pain

with pregabalin (300 mg/day or 600 mg/day) or placebo for 8 weeks. A decrease in pain of 30% or more was reported by 63% of patients who received pregabalin compared with 25% for patients who received placebo. A decrease in pain of 50% or more was reported by 50% of patients who received pregabalin and by 20% of patients who received placebo. Recently, a second double-blind, randomized study of pregabalin in 238 patients with PHN (Sabatowski et al., 2004) reported decreased interference with sleep and significant improvements in health-related quality of life in patients treated with pregabalin. In September 2004, pregabalin received an approvable letter from the FDA. Conditions required for approval were not specified. Other anticonvulsants including oxcarbazepine (Trileptal; Novartis), a N-type calcium-channel blocker, and zonisamide (Zonegran; Elan Pharma), a sodium and calcium channel blocker, are also under investigation for neuropathic pain. Selective Serotonin Reuptake Inhibitors and Selective Norepinephrine Reuptake Inhibitors Although SSRIs are generally better tolerated than TCAs, data from clinical studies of SSRIs for pain are inconsistent. SSRIs are regarded as less effective and are not considered first-line treatment. In patients with coexisting symptoms of depression, however, SSRIs may provide a useful benefit. Comorbid conditions, especially depression, anxiety, and sleep disorders, are more common in patients with neuropathic pain compared with the general population and can impact on perception and tolerance of pain. Sleep disturbances have been noted in 50% to 70% of patients with pain (Harden & Cohen, 2003). Studies of the SSRI paroxetine (Paxil; GlaxoSmithKline) and citalopram (Celexa) demonstrated their efficacy for PDN, and results suggested paroxetine may be as effective as the TCA imipramine (Sindrup, Bjerre, Dejgaard, Brosen, AaesJorgensen & Gram, 1992; Sindrup, Gram, Brosen, Eshoj, & Mogensen, 1990). Efficacy for neuropathic pain has also been reported for venlafaxine (Effexor; Wyeth Pharmaceuticals, Madison, NJ), and duloxetine (Cymbalta) which have both SSRI and selective norepinephrine inhibitor (SNRI) properties (Lilly Research Laboratories, 2004; Lithner, 2000; Kiayias, Vlachou, LakkaPapadodima, 2000; Davis & Smith, 1999) and bupropion (Wellbutrin; GlaxoSmithKline) (Semenchuk et al., 2001), which has an unknown mechanism of action (it is a weak SSRI and weak SNRI). Duloxetine was approved by the FDA in late 2004 for the treatment of painful diabetic peripheral neuropathy. A dose of 60 mg once daily significantly reduced 24-hour average pain and was effective in

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relieving pain at night in two randomized trials (PR Newswire). Systemic Lidocaine Lidocaine (Lidoject; Merz Pharmaceuticals, Greensboro, NC) may be administered parenterally for the treatment of neuropathic pain (for a review, see Edwards, 1999). Systemic lidocaine should only be used by skilled clinicians because it may cause aggravation of first- and second-degree heart conduction blocks and possible systemic local anesthetic toxicity. Mexiletine (Mexitil; Boehringer Ingelheim, Ridgefield, CT), an orally administered drug, also has systemic effects. Mexiletine is a class I antiarrhythmic drug and also has anesthetic properties. Clonidine Clonidine (Catapres; Boehringer Ingelheim), an ␣-adrenoceptor agonist, is an antihypertensive drug. Evidence from both basic and clinical studies indicates that clonidine is effective in the management of both neuropathic and physiologic pain. In pain management, it is commonly administered intrathecally or epidurally to minimize systemic side effects (Siddall, Molloy, Walker, & Rutkowski, 2000). Clonidine is available as a patch for transdermal administration which, through systemic actions, has shown efficacy in neuropathic pain due to PDN (Byas-Smith, Max, Muir, & Kingman, 1995). As a topically administered cream, clonidine also provides some relief from orofacial neuralgia–like pain (Sawynok, 2003). Skeletal Muscle Relaxants Muscle relaxants include many different agents. Their mechanism of action for analgesia remains unknown and does not appear to be related to direct relaxation of skeletal muscle (Waldman, 1994). Baclofen (Lioresal; Novartis, East Hanover, NJ), a GABA-B receptor agonist, has proven effective for neuropathic pain in a study of patients with trigeminal neuralgia (Sindrup & Jensen, 1999). Drowsiness is the most common side effect. Some skeletal muscle relaxants may produce physical dependence and have the potential for abuse. Corticosteroids A recent, randomized, double-blind study demonstrated the efficacy of methylprednisolone and lidocaine administered intrathecally in the treatment of PHN refractory to other treatment (Kotani et al., 2000). In this study, more than 80% of patients reported good or excellent pain relief. Topical Analgesics Topical analgesics for neuropathic pain are an attractive treatment option because they deliver medication

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locally and are associated with minimal side effects and drug-drug interactions (Argoff, 2003). Occasionally, local adverse effects (e.g., redness, itching) are noted. In addition to the FDA-approved 5% lidocaine patch (see above), topical treatments include capsaicin, doxepin, morphine, and isosorbide dinitrate spray. Capsaicin (Zostrix; Medicis Pharmaceuticals, Phoenix, AZ), a vanilloid compound isolated from chili peppers, is available in over-the-counter preparations. It is thought to elevate the pain threshold through depletion of substance P from the membranes of Cnociceptive fibers and through induction of calcitonin gene-related peptide (Capsaicin Study Group, 1991). Capsaicin cream 0.075% has been evaluated in the treatment of PDN, PHN, postmastectomy pain syndrome, and complex regional pain syndrome, with some benefit demonstrated (Watson, 1994). After application, there is a burning sensation with heat hyperalgesia. The burning sensation, limited pain relief, and difficulty from inadvertently spreading cream to other parts of the body caused many patients to discontinue use. It may take several weeks to achieve a therapeutic effect; clinical benefits are observed after 4 or more weeks of application, four or more times daily (Gordon, 2003). Doxepin, a TCA drug, has been available in the United Kingdom for several years as a topical formulation for the treatment of eczema. Topical application of doxepin alone or in combination with capsaicin was found to be equally effective in neuropathic pain (McCleane, 2003). Eutectic mixture of local anesthetics (EMLA; Astra Zeneca) cream is another topical treatment. EMLA contains lidocaine 2.5% with prilocaine 2.5%. Unlike the lidocaine patch, EMLA produces numbness in the skin over which it is applied. In a study of women undergoing breast cancer, who often experience neuropathic pain after surgery, perioperative application of EMLA cream provided analgesic benefit. Three months after surgery, the total incidence and intensity of chronic pain was significantly less in the group that had used EMLA perioperatively (Fassoulaki, Sarantopoulos, Melemeni, & Hogan, 2000). A prilocaine-free topical local anesthetic cream (lidocaine 4%, LMX4; Ferndale Labs, Ferndale, MI) is also available as an over-the-counter product. Advantages include a faster onset and no risk of methemoglobinemia. In a small pilot study, a topical cream containing a combination of amitriptyline (1%) and ketamine (0.5%), when used for 7 days, was effective in relieving neuropathic pain (Lynch, Clark, & Sawynok, 2003). Clinical trials have demonstrated analgesic efficacy when opioids are applied locally in certain situations (e.g., knee surgery, skin ulcers, and oral mucosi-

tis), with more controversial results in other situations. The analgesic efficacy of peripheral opioids appears to increase linearly with the duration of inflammation (Zhou, Zhang, Stein, & Schafer, 1998), and little is known about its effect on neuropathic pain. In three small studies (Twillman, Long, Cathers, & Mueller 1999; Long, Cathers, Twillman, O’Donnell, Garrigues, & Jones, 2001; Zeppetella, Paul, & Ribeiro, 2003), parenteral morphine solution mixed in amorphous wound gels was effective for skin ulcers, burn pain, and painful sacral sores. In a pilot study, isosorbide dinitrate applied in a spray form was effective in relieving the neuropathic pain and burning sensation associated with PDN (Yuen, Baker, & Rayman, 2002). Botulinum Toxin Botulinum toxin binds to nerve endings where they join muscles, and prevents the nerves from signaling muscles to contract. In preliminary clinical studies, favorable results have been observed for the treatment of a number of neuropathic pain conditions (for a review, see Argoff, 2002). These include complex regional pain syndrome type I, hyperesthesia, allodynia, spontaneous burning pain associated with cervical spinal cord injury, PHN, and brachial plexopathy. Botulinum toxin is being actively studied to further define its role as an analgesic in neuropathic pain. N-Methyl-D-Aspartate Receptor Antagonists Activation of the N-Methyl-D-Aspartate (NMDA) receptor found in the spinal cord dorsal horn causes the spinal cord neuron to become more responsive to all types of inputs, including nociception and touch, which results in central sensitization (Bennett, 2000). Blocking or antagonizing this process can reduce spontaneous pain and hyperalgesia. Two currently marketed drugs ketamine and dextromethorphan are NMDA receptor antagonists. In a small trial, dextromethorphan, at median doses of 400 mg/day, was effective for PDN (Sang, Booher, Gilron, Parada, & Max, 2002). Both dextromethorphan and ketamine often produce side effects, however, which limit their usefulness (Sang, 2000). A study of a third NMDA receptor antagonist (memantine), in neuropathic pain after amputation showed no difference between memantine and placebo on any outcome measure (Nikolajsen, Gottrup, Kristensen, & Jensen, 2000). Nonsteroidal Anti-Inflammatory Drugs The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of neuropathic pain is limited. Although prostaglandins are known to contribute to hyperalgesia after nerve injury (Syriatowicz, Hu,

Pharmacologic Management of Neuropathic Pain

Walker, & Tracey, 1999; Ma, Du & Eisenach, 2002), studies that have examined the efficacy of NSAIDs in neuropathic pain have shown minimal or no analgesic effect (Kingery, 1997; De Benedittis & Lorenzetti, 1996; Max, Schafer, Culnane, Dubner, & Gracely, 1988). Use of NSAIDs is also restricted by their potential for adverse effects including renal dysfunction and gastrointestinal ulceration. However, when inflammation is present, these medications may provide some benefit (Stanton-Hicks et al., 1998). Methadone Methadone (Dolophine; Roussel USA, Bridgewater, NJ), an opioid agonist, is an effective analgesic that is often used for the relief of severe chronic pain. Methadone also inhibits norepinephrine and serotonin reuptake and binds at NMDA receptors to modulate pain (Foley, 2003). Because of issues involving potency and the drug’s long, variable half-life, methadone is not considered as a first-line treatment for neuropathic pain, but it is increasingly used in practice. For this reason, clinical issues regarding methadone use are discussed more fully below. Patients who had been receiving opioids on a regular basis for chronic pain may sometimes experience inadequate analgesia, with side effects that limit the further escalation of dose. To maximize analgesia and minimize side effects, some clinicians choose to rotate patients to other opioids, including methadone for pain relief (Layson-Wolf et al., 2002). Patients who had previously been receiving morphine, hydromorphone, fentanyl, or levorphanol for chronic pain may find improved pain relief at doses of methadone that are as low as 10% of a calculated equianalgesic dose (Foley, 2003). A study of patients with chronic neuropathic pain reported positive results for methadone (Morley, Bridson, Nash, Miles, White, & Makin., 2003). Methadone has a prolonged half-life and slow elimination. It is lipophilic and accumulates in body tissues. When first administered, methadone may have a relatively short analgesic action (4 to 6 hours) and can be titrated daily (similar to other short-acting oral opioids). After 3 to 4 days of regular dosing, the drug’s terminal half-life can become quite prolonged (90 to 120 hours), and because it takes 3 to 5 half-life elimination periods to obtain steady state, further dose increases should rarely be done more frequently than once every 2 weeks to avoid accumulation and overdose. The dosing interval can sometime be increased to 6 to 12 hours. Methadone shares the common side effects observed with any opioid. Of particular concern, respiratory depression and sedation may occur. With re-

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TABLE 6. Nursing Considerations in Pharmacologic Management of Neuropathic Pain ● Recognition of the frequent need for multidrug treatment in neuropathic pain to address multiple underlying mechanisms, associated comorbidities of neuropathic pain (insomnia, anxiety, depression), and side effects from pain treatments ● Awareness of additive and synergistic effects and drug interactions ● The need to educate the patient and family about titration, side effects, and possible adverse effects of various medications ● The need to prepare patients for the likelihood of subsequent analgesic trials ● The need to discuss realistic expectations about optimal benefits (percentage of pain relief and functional goals) obtainable through pharmacologic approaches

peated dosing, this risk is increased because of drug accumulation, and for this reason methadone should be used cautiously, especially in elderly patients. Potential drug-drug interactions are many, but only a few have been described clinically. Methadone may interact with drugs metabolized by cytochromes P4501A2, P4502D6, and P4503A4. A partial listing of drugs that might augment methadone toxicity includes fluvoxamine, cimetidine, amiodarone, paroxetine, fluoxetine, verapamil, and tramadol (Layson-Wolf, Goode, & Small, 2002).

EVALUATING THE PATIENT’S RESPONSE: IMPLICATIONS FOR NURSING A basic understanding of the mechanisms underlying neuropathic pain and the principles of drug treatment is useful for nursing practice. General considerations for patient management are outlined in Table 6. Frequently, patients require polypharmacy to address the multiple mechanisms causing their pain as well as to treat concurrent medical conditions, comorbidities related to their pain, or side effects from pain treatments. Nurses must be cognizant of additive and synergistic effects of concurrent analgesic and/or psychotropic medications, as well as drug interactions. Patient and family education on titration, side effects, possible adverse effects of medications, the possible need for alternate analgesic trials, and the realistic expectations of treatment are essential. Not all patients with neuropathic pain will respond to pharmacologic treatment. In clinical trials of analgesic agents, response rates ranging from 30% to

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60% have been reported (see Dworkin, Backonja, et al., 2003, for a review). For those in whom treatment is successful, the magnitude of pain relief observed in these studies is an important consideration, especially in its relation to pain scales commonly used in nursing practice for patient assessment. In evaluating a clinical study, statistically significant results (based on trial data) and clinically significant results (experienced by patients) may show correlation to a small, intermediate, or high degree. In studies of chronic pain, the patient’s subjective experience of pain is often measured using the pain intensity numeric rating scale (PI-NRS; 0 ⫽ no pain, 10 ⫽ worst possible pain) at baseline and after treatment. In one study, the clinical importance of the PINRS was investigated by correlating it with scores of a subjective measure—patient global impression of change (PGIC). In this analysis, patients who reported “much improved” or “very much improved” PGIC scores were considered to have clinically significant pain relief. A change in PI-NRS score of ⫺1.74 (or a percent change of ⫺27.9%) was correlated with a PGIC score of “much improved” or “very much improved” (Farrar, Young, LaMoreaux, Werth, & Poole, 2001). In another study, a 33% decrease in pain from a given treatment was judged to be a reasonable standard for determining a change in pain intensity that represented clinically important pain relief from a patient’s perspective (Jensen, 2003). Taken together, these findings suggest that apparently minor changes in pain scores of 1 to 2 points may, in fact, be very significant to the patient. The definition of a significant level of pain relief from the patient’s perspective is an important piece of clinical information that can facili-

tate improved patient care. It is also critical to remember that the efficacy of any pain treatment cannot be judged solely on the basis of pain intensity ratings. Rather, the evaluation of the effectiveness of any treatment should be based (in addition to pain relief) on its impact on function, sleep, quality of life, and the burden of treatment (e.g., cost, convenience, and side effects).

CONCLUSIONS At present, available therapies for neuropathic pain, both pharmacologic and nonpharmacologic, may sometimes be inadequate, at least in some patients. The use of currently available agents continues to evolve based on emerging clinical trial data that shows both their positive and negative effects. In addition to current treatment options, several newer agents are under development for the treatment of neuropathic pain. As clinical research advances, new drugs will become available, with each holding promise for the future. Because of the complexities in the underlying mechanisms, rational polypharmacy is often inevitable in the treatment of neuropathic pain. Knowledge of current and emerging pharmacologic therapies and their effects is critical to the delivery of safe and effective treatment. Ongoing patient assessments remain a key element of nursing practice and the management of neuropathic pain. ACKNOWLEDGMENT The authors would like to thank Misha Backonja, MD for review of this manuscript.

REFERENCES Ahmad, M., Goucke, C. R. (2002). Management strategies for the treatment of neuropathic pain in the elderly. Drugs and Aging, 19, 929-945. American Pain Society (2004). Guideline for the management of cancer pain, clinical practice guideline #3. Glenview, IL: American Pain Society. Argoff, C. E. (2002). A focused review on the use of botulinum toxins for neuropathic pain. Clinical Journal of Pain, 18(Suppl.), S177-S181. Argoff, C. E. (2003). Topical analgesics: A review of recent clinical trials and their application to clinical practice. Advanced Studies in Medicine, 3, S643-S647. Backonja, M., Beydoun, A., Edward, K. R., Schwartz, S. L., Fonseca, V., Hes, M., et al. (1998). Gabapentin for the sympathetic treatment of painful neuropathy in patients with diabetes mellitus. Journal of the American Medical Association, 280, 1831-1836.

Backonja, M., Glanzman, R. L. (2003). Gabapentin for neuropathic pain: Evidence from randomized placebo-controlled clinical trials. Clinical Therapeutics, 25, 81-104. Bailey, K. P. (2004). Serotonin syndrome and the use of SSRIs. Journal of Psychosocial Nursing & Mental Health Services, 42, 16-20. Bajwa, Z. H., Ho, C. C. (2001). Herpetic neuralgia. Use of combination therapy for pain relief in acute and chronic herpes zoster. Geriatrics, 56, 18-24. Barbano, R. L., Herrmann, D. N., Hart-Gouleau, S., Pennella-Vaughan, J., Lodewick, P.A., Dworkin, R. H. (2004). Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Archives of Neurology, 61, 914-918. Bennett, G. J. (2000). Update on the neurophysiology of pain transmission and modulation: Focus on the NMDAreceptor. Journal of Pain and Symptom Management, 19(Suppl.), S2-S6.

Pharmacologic Management of Neuropathic Pain

Beydoun, A., Backonja, M-M. (2003). Mechanistic stratification of antineuralgic agents. Journal of Pain and Symptom Management, 25(Suppl.), S18-S30. Byas-Smith, M. G., Max, M. B., Muir, J., Kingman, A. (1995). Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design. Pain, 60, 267-274. Capsaicin Study Group. (1991). Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. Archives of Internal Medicine, 151, 2225-2229. Christo, P. J. (2003). Opioid effectiveness and side effects in chronic pain. Anesthesiology Clinics of North America, 21, 699-713. Davis, J. L., Smith, R. L. (1999). Painful peripheral diabetic neuropathy treated with venlafaxine HCl extended release capsules. Diabetes Care, 22, 1909-1910. DeBenedittis, G., Lorenzetti, A. (1996). Topical aspirin/ diethyl ether mixture versus indomethacin and diclofenac/ diethyl ether mixtures for acute postherpetic neuralgia and postherpetic neuralgia: A double-blind crossover placebocontrolled study. Pain, 65, 45-61. Dellemijn, P. (1999). Are opioids effective in relieving neuropathic pain? Pain, 80, 453-462. Dworkin, R. H., Backonja, M., Rowbotham, M. C., Allen, R. R., Argoff, C. R., Bennett, G. J., et al. (2003). Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Archives of Neurology, 60, 15241534. Dworkin, R. H., Corbin, A. E., Young, J. P., Sharma, U., LaMoreaux, L., Bockbrader, H., et al. (2003). Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo controlled trial. Neurology, 60, 1274-1283. Edwards, A. D. (1999). The role of systemic lidocaine in neuropathic pain management. Journal of Intravenous Nursing, 22, 273-279. Eisenberg, E., Luria, Y., Braker, C., Daoud, D., Ishay, A. (2001). Lamotrigine reduces painful diabetic neuropathy: A randomized, controlled study. Neurology, 57, 505-509. Farrar, J. T., Young, J. P., LaMoreaux, L., Werth, J. L., Poole, R. M. (2001). Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain, 94, 149-158. Fassoulaki, A., Sarantopoulos, C., Melemeni, A., Hogan, Q. (2002). EMLA reduces acute and chronic pain after breast surgery for cancer. Regional Anesthesia and Pain Medicine, 25, 350-355. Fields, H. L., Rowbotham, M., Baron, R. (1998). Postherpetic neuralgia: Irritable nociceptors and deafferentation. Neurobiology and Disease, 5, 209-227. Foley, K. M. (2003). Opioids and chronic neuropathic pain. New England Journal of Medicine, 348, 1279-1281. Galer, B. S., Rowbotham, M. C., Perander, J., Friedman, E. (1999). Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: Results of an enriched enrollment study. Pain, 80, 533538. Gammaitoni, A. R., Alvarez, N. A., Galer, B. S. (2002). Pharmacokinetics and safety of continuously applied lidocaine patches 5%. American Journal of Health-System Pharmacy, 59, 2215-2220. Gilron, I., Bailey, J. M. (2003). Trends in opioid use for chronic neuropathic pain: A survey of patients pursuing

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enrollment in clinical trials. Canadian Journal of Anaesthesia, 50, 42-47. Gimbel, J. S., Richards, P., Portenoy, R. K. (2003). Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial. Neurology, 60, 927-934. Glassman, A. H., Roose, S. P. (1994). Risks of antidepressants in the elderly: Tricyclic antidepressants and arrhythmia—Revising risks. Gerontology, 40(Suppl. 1), 15-20. Gordon, D. B. (2003). Nonopioid and adjuvant analgesics in chronic pain management: Strategies for effective use. Nursing Clinics of North America, 38, 447-464. Harati, Y., Gooch, C., Swenson, M., Edelman, S., Greene, D., Raskin, P., et al. (1998). Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology, 50, 1842-1846. Harden, N., Cohen, M. (2003) Unmet needs in the management of neuropathic pain. Journal of Pain and Symptom Management, 25(Suppl.), S12-S17. Hord, A. H., Denson, D. D., Chalfoun, A. G., Azevedo, M. I. (2003). The effect of systemic zonisamide (Zonegran) on thermal hyperalgesia and mechanical allodynia in rats with an experimental mononeuropathy. Anesthesia and Analgesia, 96, 1700-1706. Huse, E., Larbig, W., Flor, H., Birbaumer, N. (2001). The effect of opioids on phantom limb pain and cortical reorganization. Pain, 90, 47-55. Jamison, R. N., Anderson, K. O., Peeters-Asdourian, C., Ferrante, F. M. (1994). Survey of opioid use in chronic non-malignant pain patients. Regional Anesthesia, 19, 225230. Jensen, M. P. (2003). The validity and reliability of pain measures in adults with cancer. Journal of Pain, 4, 2-21. Jensen, T. S., Gottrup, H., Sindrup, S. H., Bach, F. W. (2001). The clinical picture of neuropathic pain. European Journal of Pharmacology, 429, 1-11. Kiayias, J. A., Vlachou, E. D., Lakka-Papadodima, E. (2000). Venlafaxine HCl in the treatment of painful peripheral diabetic neuropathy. Diabetes Care, 23, 699. Kingery, W. S. (1997). A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain, 73, 123-130. Kotani, N., Kushikata, T., Hashimoto, H., Kimura, F., Muroaka, M., Yodono, M., et al. (2000). Intrathecal methylprednisolone for intractable postherpetic neuralgia. New England Journal of Medicine, 343, 1514-1519. Layson-Wolf, C., Goode, J. V., Small, R. E. (2002). Clinical use of methadone. Journal of Pain & Palliative Care Pharmacotherapy, 16, 29-59. Lewis, K. S., Han, N. H. (1997). Tramadol: A new centrally acting analgesic. American Journal of Health-System Pharmacy, 54, 643-652. Lilly Research Laboratories. Data on file. (2004). Lithner, F. (2000). Venlafaxine in treatment of severe painful peripheral diabetic neuropathy. Diabetes Care, 23, 1710-1711. Liu, B., Anderson, G., Mittmann, N., To, T., Axcell, T., Shear, N. (1998). Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet, 351, 1303-1307. Long, T. D., Cathers, T. A., Twillman, R., O’Donnell, T., Garrigues, N., Jones, T. (2001). Morphine-Infused silver sulfadiazine (MISS) cream for burn analgesia: A pilot study. Journal of Burn Care & Rehabilitation, 22, 118-123.

32

Gordon and Love

Lynch, M. E., Clark, A. J., Sawynok, J. (2003). A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clinical Journal of Pain, 19, 323-328. Ma, W., Du, W., Eisenach, J. C. (2002). Role of both spinal cord COX-1 and COX-2 in maintenance of mechanical hypersensitivity following peripheral nerve injury. Brain Research, 937, 94-99. Mahlberg, R., Kunz, D., Sasse, H., Kircheiner, J. (2004). Serotonin syndrome with tramadol and citalopram. American Journal of Psychiatry, 161, 1129. Max, M. B. (1995). Thirteen consecutive well-designed randomized trials show that antidepressants reduce pain in diabetic neuropathy and postherpetic neuralgia. Pain Forum, 4, 248-253. Max, M. B., Schafer, S. C., Culnane, M., Dubner, R., Gracely, R. H. (1988). Association of pain relief with drug side effects in post-herpetic neuralgia: A single-dose study of clonidine, codeine, ibuprofen and placebo. Clinical Pharmacology and Therapeutics, 43, 363-371. McCleane, G. (2003). Topical use of nitrates, capsaicin, and tricyclic antidepressants for pain management. Advanced Studies in Medicine, 3, S631-S634. Meier, T., Wasner, G., Faust, M., Kuntzer, T., Ochsner, F., Hueppe, M., et al. (2003). Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: A randomized, double-blind, placebo-controlled study. Pain, 106, 151-158. Morley, J. S., Bridson, J., Nash, T. P., Miles, J. B., White, S., Makin, M. K. (2003). Low-dose methadone has an analgesic effect in neuropathic pain: A double-blind randomized controlled crossover trial. Palliative Medicine, 17, 576-587. Nikolajsen, L., Gottrup, H., Kristensen, A. G. D., Jensen, T. S. (2000). Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: A randomized, double-blinded, crossover study. Anesthesia and Analgesia, 91, 960-966. Pasero, C., and McCaffery, M. (2003). Tramadol: An atypical, second-line opioid analgesic treats stable, mild to moderate pain. American Journal of Nursing, 103, 71-73. PR Newswire Association, Inc. September 7, 2004. URL: http//www.prnewswire.com. Raja, S. N., Haythornthwaite, J. A., Pappagallo, M., Clark, M. R., Travison, T. G., Sabeen, S., et al. (2002). Opioids versus antidepressants in postherpetic neuralgia. A randomized, placebo-controlled trial. Neurology, 59, 10151021. Roose, S. P., Laghrissi-Thode, F., Kennedy, J. S., Nelson, J. C., Bigger, Jr., J. T.Pollock, B. G., et al. (1998). Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. Journal of the American Medical Association, 279, 287-291. Rowbotham, M. C., Davies, P. S., Verkempinck, C., Galer, B. S. (1996). Lidocaine patch: Double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain, 65, 39-44. Rowbotham, M., Harden, N., Stacey, B., Bernstein, P., Magnus-Miller, L. (1998). Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. Journal of the American Medical Association, 280, 215-224. Rowbotham, M. C., Twilling, L., Davies, P. S., Reisner, L., Taylor, K., Mohr, D. (2003). Oral opioid therapy for

chronic peripheral and central neuropathic pain. New England Journal of Medicine, 348, 1223-1232. Sabatowski, R., Gálvez, R., Cherry, D. A., Jacquot, F., Vincent, E., Maisonobe, P., et al., for the 1008-045 Study Group. (2004). Pregabalin reduces pain and improves mood disturbances in patients with post-herpetic neuralgia: Results of a randomized, placebo-controlled trial. Pain, 109 26-35. Sang, C. N., Booher, S., Gilron, I., Parada, S., Max, M. B. (2002). Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: Efficacy and dose-response trials. Anesthesiology, 96, 1053-1061. Sang, C. N. (2000). NMDA-receptor antagonists in neuropathic pain: Experimental methods to clinical trials. Journal of Pain and Symptom Management, 19(Suppl), S21S25. Sawynok, J. (2003). Recent findings surrounding topical antidepressants as analgesics and review of existing and emerging topical analgesics. Advanced Studies in Medicine, 3, S635-S641. Sawynok, J., Esser, M. J., Reid, A. R. (2001). Antidepressants as analgesics: An overview of central and peripheral mechanisms of action. Journal of Psychiatry & Neuroscience, 26, 21-29. Semenchuk, M. R., Sherman, S., Davis, B. (2001). Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology, 57, 1583-1588. Siddall, P. J., Molloy, A. R., Walker, S., Rutkowski, S.B. (2000). The efficacy of intrathecal morphine and clonidine in the treatment of pain after spinal cord injury. Anesthesia and Analgesia, 91, 1493-1498. Simpson, D. M., McArthur, J. C., Olney, R., Clifford, D., So Y., Ross, D., et al., for the Lamotrigine HIV Neuropathy Study team. (2003). Lamotrigine for HIV-associated painful sensory neuropathies: A placebo-controlled trial. Neurology, 60, 1508-1514. Simpson, D. M., Olney, R., McArthur, J. C., Khan, A., Godbold, J., Ebel-Frommer, K., for the Lamotrigine HIV Neuropathy Study Group. (2000). A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology, 54, 2115-2119. Sindrup, S. H., Andersen, G., Madsen, C., Smith, T., Brosen, K., Jensen, T. S. (1999). Tramadol relieves pain and allodynia in polyneuropathy: A randomized doubleblind controlled trial. Pain, 83, 85-90. Sindrup, S. H., Bjerre, U., Dejgaard, A., Brosen, K., AaesJorgensen, T., Gram, L. F. (1992). The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther, 52, 547-552. Sindrup, S. H., Gram, L. F., Brosen, K., Eshoj, O., Mogensen, E. F. (1990). The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain, 42, 135-144. Sindrup, S. H., Jensen, T. S. (1999). Efficacy of pharmacological treatments of neuropathic pain: An update and effect related to mechanism of drug action. Pain, 83, 389400. Staats, P. S., Markowitz, J., Schein, J. (2004). Incidence of constipation associated with long-acting opioid therapy: A comparative study. Southern Medical Journal, 97, 129134. Stanton-Hicks, M., Baron, R., Boas, R., Gordh, T., Harden, N., Hendler, N., et al. Complex regional pain

Pharmacologic Management of Neuropathic Pain

syndromes: Guidelines for therapy. Clinical Journal of Pain, 14, 55–166. Syriatowicz, J. P., Hu, D., Walker, J. S., Tracey, D. J. (1999). Hyperalgesia due to nerve injury: Role of prostaglandins. Neuroscience, 94, 587-594. Turk, D. C., Brody, M. C., Okifuji, E. A. (1994). Physicians’ attitudes and practices regarding the long-term prescribing of opioids for non-cancer pain. Pain, 59, 201-208. Twillman, R. K., Long, T. D., Cathers, T. A., Mueller, D. W. (1999). Treatment of painful skin ulcers with topical opioids. Journal of Pain and Symptom Management, 17, 288-292. Vestergaard, K., Andersen, H., Gottrup, H., Kristensen, B. T., Jensen, T. S. (2001). Lamotrigine for central poststroke pain: A randomized controlled trial. Neurology, 56, 184-190. Waldman, H. J. (1994). Centrally acting skeletal muscle relaxants and associated drugs. Journal of Pain and Symptom Management, 9, 434-441. Watson, C. P. N. (1994). Topical capsaicin as an adjuvant analgesic. Journal of Pain and Symptom Management, 9, 425-433.

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Watson, C. P. N., Babul, N. (1998). Efficacy of oxycodone in neuropathic pain: A randomized trial in postherpetic neuralgia. Neurology, 50, 1837-1841. Watson, C. P., Moulin, D., Watt-Watson, J., Gordon, A., Eisenhoffer, J. (2003). Controlled-release oxycodone relieves neuropathic pain: A randomized controlled trial in painful diabetic neuropathy. Pain, 105, 71-78. Yuen, K. C., Baker, N. R., Rayman, G. (2002). Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: A double-blind placebo-controlled cross-over study. Diabetes Care, 25, 1699-1703. Zeppetella, G., Paul, J., Ribeiro, M. D. (2002). Analgesic efficacy of morphine applied topically to painful ulcers. Journal of Pain and Symptom Management, 25, 555-558. Zhou, L., Zhang, Q., Stein, C., Schafer, M. (1998). Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia. Journal of Pharmacology and Experimental Therapeutics, 286, 1000-1006. Zochodne, D. W., Max, M. B. (2003). An old acquaintance. Opioids in neuropathic pain. Neurology, 60, 894895.